Senolytic Therapy for Frailty

Overseen By Gregory T. Armstrong, MD, MSCE

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: CYP3A4 drugs, Anticoagulants

Disqualifiers: HIV, Hepatitis B/C, Anemia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

Duration: 32 days

120 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a first-in survivor pilot study with the goal of establishing preliminary evidence of efficacy, safety, and tolerability of two senolytic regimens to reduce markers of cellular senescence (primary outcome: p16\^INK4a) and improve frailty (primary outcome: walking speed) in adult survivors of childhood cancer. If successful, this pilot would provide the preliminary evidence needed for a phase 2, randomized, placebo-controlled trial to establish efficacy. Primary Objective * The primary aim of this proposal is to test the efficacy of two, short duration senolytic regimens: 1) combination of Dasatinib plus Quercetin and 2) Fisetin alone, to improve walking speed and decrease senescent cell abundance in blood (p16\^INKA): * Primary endpoints of this trial will be change in walking speed and senescent cell abundance in blood (p16\^INK4A) determined at baseline and again at 60 days, within an individual arm. Extended follow up at 150 days will assess the permanence of change after completion of the trial. Secondary endpoints of this trial will be effect of intervention on additional measures of frailty (beyond walking speed; Fried criteria) and on other cell senescence markers, markers of inflammation, insulin resistance, bone resorption, and cognitive function. Secondary Objectives The secondary aim is to test the safety and tolerability of two different senolytic therapies. Exploratory Objectives * To compare the efficacy of the two senolytic regimens in improving walking speed and decreasing senescent cell abundance * To evaluate the longitudinal pattern in measures of frailty.

Do I need to stop my current medications for the trial?

The trial requires you to stop taking certain medications, especially those that affect specific enzymes (CYP3A4, CYP2C8, CYP2C9, or CYP2D6) or if you are on anticoagulants or antimicrobial agents. If you are on anticoagulants or antiplatelet agents, you may need to pause them during the 2-3 day drug dosing period, but you can resume them afterward.

What data supports the effectiveness of the drug Dasatinib plus Quercetin for frailty?

Research in mice has shown that the combination of Dasatinib and Quercetin can improve frailty characteristics, motor and cognitive functions, and reduce signs of aging in the brain. Additionally, these drugs have been found to reduce senescent cells, which are linked to aging and frailty, in other studies. ^{1 2 3 4 5}

Is senolytic therapy with dasatinib and quercetin safe for humans?

In early clinical trials, dasatinib and quercetin were generally well-tolerated in humans, with no early discontinuations and only mild to moderate side effects reported. These findings suggest a favorable safety profile, but more extensive studies are needed to confirm these results. ^{1 2 5 6 7}

How is the drug Dasatinib plus Quercetin, Fisetin unique for treating frailty?

This drug combination is unique because it uses senolytic agents, which target and eliminate senescent cells (cells that have stopped dividing and can contribute to aging and frailty), potentially addressing the root cause of frailty rather than just its symptoms. Unlike standard treatments, this approach aims to improve overall health by reducing the burden of these harmful cells. ^{8 9 10 11 12}

Research Team

Gregory T. Armstrong, MD, MSCE

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

Adults who survived childhood cancer and are now frail (meeting at least 3 of 5 specific health criteria), over 18 years old, more than 5 years post-diagnosis, with certain blood markers. They must be able to take oral meds, not pregnant or nursing, agree to use contraception due to teratogenic risks of Dasatinib, have no severe heart issues or anemia, and not on conflicting medications.

Inclusion Criteria

QTc <450 milliseconds in electrocardiogram

I am part of SJLIFE and was diagnosed over 5 years ago.

My test shows low levels of a specific protein in my immune cells.

Exclusion Criteria

I am currently taking blood thinners or antibiotics.

Pregnant or nursing at time of enrollment/during the study

I am not currently receiving treatment for any cancer except non-melanoma skin cancers.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Dasatinib plus Quercetin or Fisetin to reduce senescence and improve frailty

32 days

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

150 days

2 visits (in-person)

Treatment Details

Interventions

• Dasatinib plus Quercetin
• Fisetin

Trial Overview The trial is testing two treatments aimed at reducing cell aging and improving physical function in adult survivors of childhood cancer. One group will receive a combination of drugs called Dasatinib plus Quercetin; the other will get Fisetin alone. The main goals are better walking speed and fewer senescent cells in the blood.

Participant Groups

Group I: Dasatinib plus Quercetin Active Control 1 Intervention

Day 0 (30 per arm, randomization stratified by sex and age) At the visit on day 7, blood CD3+ T lymphocyte p16\^INK4A mRNA and other markers of inflammation and senescence will be accessed to verify that senescent cells have been cleared by the intervention. Post-treatment follow-up will occur on days 60 for (primary endpoints) and day 150 for secondary evaluation. Day 150 will assess the permanence of change after completion of the trial.

Group II: Fisetin Active Control 1 Intervention

Day 0 (30 per arm, randomization stratified by sex and age) At the visit on day 7, blood CD3+ T lymphocyte p16INK4A mRNA and other markers of inflammation and senescence will be accessed to verify that senescent cells have been cleared by the intervention. Post-treatment follow-up will occur on days 60 for (primary endpoints) and day 150 for secondary evaluation. Day 150 to will assess the permanence of change after completion of the trial.

Dasatinib plus Quercetin is already approved in European Union, United States for the following indications:

Approved in European Union as Sprycel for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia

Approved in United States as Sprycel for:

• Chronic Myelogenous Leukemia
• Acute Lymphoblastic Leukemia

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study using SAMP10 mice, which model brain aging, the combination of dasatinib and quercetin significantly improved frailty, motor, and cognitive functions compared to a control group, indicating potential benefits of senolytic therapy in aging.

SAMP10 mice exhibited greater frailty characteristics than normal aging controls (SAMR1), and the combination therapy not only reduced these frailty markers but also positively affected the senescent phenotype in the hippocampus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib plus quercetin attenuates some frailty characteristics in SAMP10 mice. Ota, H., Kodama, A.[2022]

In a 12-week pilot study involving 5 participants with early-stage Alzheimer's disease, the combination of dasatinib and quercetin was well-tolerated, showing safety and feasibility without significant adverse effects or early discontinuations.

The treatment successfully penetrated the central nervous system, with dasatinib detected in cerebrospinal fluid, suggesting potential for targeting cellular senescence in Alzheimer's, although cognitive improvements were not observed in this small trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease. Gonzales, MM., Garbarino, VR., Kautz, T., et al.[2023]

Senolytic drugs, particularly fisetin, have shown promise in reducing age-related bone density loss in a progeria mouse model, suggesting they may help combat osteoporosis in aging individuals.

The study highlights the potential of targeting senescent cells, which accumulate with age and contribute to various age-related conditions, as a strategy to improve bone health and overall quality of life in the elderly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24 -/- Progeria Mouse Model. Hambright, WS., Mu, X., Gao, X., et al.[2023]

Fisetin was identified as the most potent senolytic flavonoid among 10 tested, effectively reducing senescence markers in both murine and human tissues, indicating its potential for treating age-related conditions.

Treatment with fisetin in aged mice not only improved tissue health and reduced age-related pathology but also extended their median and maximum lifespan, suggesting promising implications for human clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin is a senotherapeutic that extends health and lifespan. Yousefzadeh, MJ., Zhu, Y., McGowan, SJ., et al.[2021]

The study identified six new potential senolytic compounds, including natural products like baicalein and luteolin, which may help reduce senescent cells and inflammation associated with aging.

This research utilized advanced computational methods to analyze over 40,000 molecules, marking the first proposal of these specific compounds as having senolytic activity, although further experimental validation is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural Products as a Major Source of Candidates for Potential Senolytic Compounds obtained by in silico Screening. Barrera-Vázquez, OS., Magos-Guerrero, GA., Escobar-Ramírez, JL., et al.[2023]

Dasatinib and quercetin (D&Q) effectively reduce markers of cellular senescence and inflammation in aging adipose tissue, which may help alleviate chronic inflammation associated with age-related diseases.

D&Q treatment improved metabolic functions in old mice, including better fasting blood glucose levels and glucose tolerance, suggesting potential for therapeutic use in combating metabolic dysfunction in aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. Islam, MT., Tuday, E., Allen, S., et al.[2023]

The phase I clinical trial involving 5 early-stage Alzheimer's patients demonstrated that the senolytic therapy dasatinib and quercetin was well-tolerated, with no early discontinuations and confirmed CNS penetrance of dasatinib in cerebrospinal fluid.

While the treatment did not show significant cognitive improvements, it provided safety data and insights into potential senolytic effects, indicating a need for further studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial. Gonzales, MM., Garbarino, VR., Kautz, TF., et al.[2023]

A clinical study involving 56 volunteers demonstrated that the generic dasatinib tablet (YiNiShu®) is bioequivalent to the branded version (Sprycel®) under both fasting and fed conditions, indicating similar pharmacokinetic profiles.

Both dasatinib formulations showed a good safety profile, confirming that patients can expect comparable efficacy and safety when using either version of the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. Wang, Y., Xue, J., Su, Z., et al.[2023]

Dasatinib is an effective targeted therapy for chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemia, showing strong hematologic, cytogenetic, and molecular responses in patients resistant or intolerant to imatinib.

Despite its efficacy, dasatinib can cause significant side effects like myelosuppression and pleural effusions, particularly in advanced-phase patients; however, recent dose optimization has reduced these adverse events without affecting the drug's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. Cony-Makhoul, P., Bergeron, A., Corm, S., et al.[2015]

A highly sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to accurately quantify dasatinib and its active metabolites in human plasma, validated over a concentration range of 1.00-1000 ng/mL.

The assay demonstrated excellent precision and accuracy, with high recovery rates and minimal matrix effects, making it suitable for pharmacokinetic studies of dasatinib in patients with chronic myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A validated LC-MS/MS assay for the simultaneous determination of the anti-leukemic agent dasatinib and two pharmacologically active metabolites in human plasma: application to a clinical pharmacokinetic study. Furlong, MT., Agrawal, S., Hawthorne, D., et al.[2015]

In a study of 48 older patients with type 2 diabetes, dasatinib, a senolytic agent, led to a significant reduction in serum glucose levels by 43.7 mg/dL compared to imatinib, suggesting its potential as an effective antidiabetic treatment.

Patients treated with dasatinib also experienced a notable reduction in hemoglobin A1c levels and required fewer daily insulin units, indicating that dasatinib may offer comparable benefits to standard diabetes medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antidiabetic Effects of the Senolytic Agent Dasatinib. Salaami, O., Kuo, CL., Drake, MT., et al.[2022]

Dasatinib, a multiple kinase inhibitor, is rapidly absorbed in the body after oral administration, with a peak concentration reached in about 30 minutes and a short elimination half-life of less than 4 hours, indicating efficient absorption and metabolism.

Most of dasatinib is eliminated through feces (85%), and while several metabolites are formed, they are not expected to significantly contribute to the drug's therapeutic effects, as the active metabolites do not show strong inhibitory activity against key kinases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism and disposition of dasatinib after oral administration to humans. Christopher, LJ., Cui, D., Wu, C., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Dasatinib plus quercetin attenuates some frailty characteristics in SAMP10 mice. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24 -/- Progeria Mouse Model. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Fisetin is a senotherapeutic that extends health and lifespan. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Natural Products as a Major Source of Candidates for Potential Senolytic Compounds obtained by in silico Screening. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. [2023]

9. France pubmed.ncbi.nlm.nih.gov

[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. [2015]

10. England pubmed.ncbi.nlm.nih.gov

A validated LC-MS/MS assay for the simultaneous determination of the anti-leukemic agent dasatinib and two pharmacologically active metabolites in human plasma: application to a clinical pharmacokinetic study. [2015]

11. England pubmed.ncbi.nlm.nih.gov

Antidiabetic Effects of the Senolytic Agent Dasatinib. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Metabolism and disposition of dasatinib after oral administration to humans. [2015]